It is currently believed that vitamin A, retinol, is biologically inert and that its myriad of biological functions are exerted by active metabolites: the visual chromophore 11-cis-retinaldehyde, and retinoic acids, which regulate gene expression by activating specific nuclear hormone receptors. Surprisingly, our preliminary data suggest that retinol is a transcriptional regulator in its own right. Retinol circulates in blood bound to serum retinol- binding protein (RBP) but it must dissociate from the protein prior to entering target cells. It was recently shown that an integral plasma membrane protein termed STRA6 binds RBP and mediates the uptake of retinol into cells. Our preliminary results demonstrate however that, in addition to its function as a vitamin A transporter, STRA6 is a ligand-activated cell surface receptor which activates a JAK/STAT pathway in response to binding retinol-RBP. Specifically, the data indicate that, association of STRA6 with retinol-bound RBP results in phosphorylation and activation of STATs, which, in turn, induce the transcription of specific STAT target genes. Studies proposed here will address the hypothesis that retinol can regulate gene transcription by activating a signalling pathway mediated by an RBP/STRA6/STAT pathway. We further propose to elucidate its involvement of this pathway in regulation of lipid homeostasis and insulin responses and in control of cell growth and survival. The results of these studies may point at novel targets for therapeutic approaches in treatment of diabetes and cancer.